Project Summary ? Administrative Core (Core A) The Administrative Core coordinates business, scheduling, and organizational matters, and facilitates scientific collaborations among the projects and cores, and regular meetings with the External Advisory Committee (EAC). The Director and Associate Director, along with an Executive Committee of Project and Core Leaders, provide day-to-day leadership of the program project. EAC provides long-term guidance on scientific and organizational matters. Although it is possible to make progress on the mechanism of the ketogenic diet benefit and Shc depletion benefit in single laboratories, it is much more likely that an integrative understanding of mechanism and biomarkers will be achieved by bringing together a cohort of experts in the field, thereby producing a collaborative analysis using several different techniques and working at multiple levels of biological organization. The interdisciplinary and international nature of this Program Project will require strong organizational leadership from the Administrative Core to further support the cross-fertilization among projects. The overarching hypothesis of the Program is Continuous, intermittent, and supplement-driven therapeutic ketosis extends functional longevity and ameliorates Alzheimer's disease. The aims include: 1) provide structure to coordinate research and promote interactions; 2) monitor and regularly review the quality of research and prepare progress reports; 3) manage the fiscal components of the Program Project; 4) facilitate publications, presentations, and the dissemination of research results; 5) organize annual meetings of project members and an external review committee; and 6) coordinate and monitor data and resource sharing, including Milan-Davis resource transfers. In total, the Administrative Core provides the organizing energy and structure for a synergistic understanding of the functional preservation and longevity benefits of the ketogenic diet, and ketomimetics, and of Shc inhibition. We provide as an example of our success a recent publication in Cell Metabolism that demonstrates the isocaloric ketogenic diet extends late-life functions and longevity in mice. This required recognition of the novelty of our findings, repositioning of resources, and putting together the appropriate collaborators to demonstrate an impactful new mechanism of lifespan extension that may have significant translatability to humans.